The present invention relates to a process for preparing a 1-substituted 5-hydroxymethylimidazole of the formula: 
, wherein
R represents alkyl, hydroxyalkyl, allyl, or substituted or unsubstituted arylmethyl or diarylmethyl, and preferably, C1-4alkyl, hydroxyC1-4alkyl, allyl, benzyl, substituted benzyl such as halogen-substituted benzyl or 3,4-dioxymethylenebenzyl, or 2-arylmethyl.
More specifically, the present invention relates to a process for preparing compound of the above formula (1) from a 1-substituted 2-mercapto-5-hydroxymethylimidazole of the formula: 
, wherein R is as defined above, which is prepared by reacting 1,3-dihydroxyacetone dimer of the formula: 
, with an acid addition salt of amine of the formula:
RNH2xe2x80x83xe2x80x83(4)
, wherein R is as defined above, and thiocyanate of the formula:
xe2x80x83Mxe2x80x94SCNxe2x80x83xe2x80x83(5)
, wherein M represents alkali metal, in the presence of a transition metal catalyst such as tungstic acid, etc. and an oxidizing agent.
The 1-substituted 5-hydroxymethylimidazole of the formula (1) and its intermediate, i.e. 1-substituted 2-mercapto-5-hydroxymethylimidazole of the formula (2) are key intermediates known to be useful for preparing various anticancer agents under development, especially, farnesyl transferase inhibitors[J. S. Ko, et al., PCT WO99/05 1 17 A1 19990204, p129].
Various processes for the preparation of the compound of the formula (2) have already been known in the literature. For example, according to the process disclosed in E-P 146228B1, 1985, the 1-substituted 2-mercapto-5-hydroxymethylimidazole is obtained in the yield of 68.2% as a pale brown powder by reacting 1,3-dihydroxyacetone dimer of the formula: 
, as the starting material, with amine of the formula:
RNH2xe2x80x83xe2x80x83(4)
, wherein R represents alkyl, allyl, arylmethyl or diarylmethyl, and thiocyanate of the formula:
Mxe2x80x94SCNxe2x80x83xe2x80x83(5)
, wherein M represents potassium,
in the mixture of an organic acid and a lower alcohol solvent.
However, under the above reaction conditions, there are some problems associated with the isolation of the product in good purity since an unidentified black tar is formed as a by-product and turned out to be difficult to purify.
For preparing compound of the formula (1) from compound of the formula (2), the known process, an oxidative desulfurization is conventionally performed by warming compound of the formula (2) in the presence of concentrated nitric acid, with or without the catalytic amount of nitrite[R. G. Jones, J. Amer. Chem. Soc., 1949, 71, 383]. This method is useful in the laboratory scale preparation. However, this process has some problems associated with safety in the industrial scale. These are evolution of environmentally toxic nitrogen oxide gas and difficult control of the reaction. In addition, if the compound of the formula (2) has an aromatic functionality, electrophilic aromatic nitration reaction on the aromatic ring is accompanied as a side reaction.
The present inventors performed extensive studies to develop a novel process for the preparation of a 1-substituted 5-hydroxymethylimidazole and its intermediate, a 1-substituted 2-mercapto-5-hydroxymethylimidazole. As a result, they have identified that the problems of the previous process for preparing compound of the formula (2) could be removed by replacing amine by its acid addition salt. That is, if the acid addition salt of amine such as ammonium chloride is used, the formation of the colored by-products are eradicated completely. Therefore, the desired compound, compound of the formula (2) can be obtained in high purity and yield.
In addition, since there are few practical examples of oxidative cleavage of thiol group, which allows to prepare compound of the formula (1) from compound of the formula (2), the present inventors made a research to develop a new process which could be viable in the industrial scale. Finally, they have identified that the desired imidazole derivative can be obtained in high purity under safe and environmentally benign reaction conditions by employing a transition metal catalyst and an oxidizing agent such as hydrogen peroxide and thus, completed the present invention.
Therefore, an object of the present invention is to provide a new process for the preparation of a 1-substituted 5-hydroxymethylimidazole of the formula (1) from 1-substituted 2-mercapto-5-hydroxymethyl imidazole of the formula (2).
The present invention relates to a process for preparing 1-substituted 5-hydroxymethylimidazole of the formula: 
, wherein R represents alkyl, hydroxyalkyl, allyl, or substituted or unsubstituted arylmethyl or diarylmethyl, and preferably, C1-4alkyl, hydroxyC1-4alkyl, allyl, benzyl, substituted benzyl such as halogen-substituted benzyl or 3,4-dioxymethylenebenzyl, or 2-arylmethyl,
comprising the steps of reacting 1,3-dihydroxyacetone dimer of the formula: 
, with an acid addition salt of amine of the formula:
RNH2xe2x80x83xe2x80x83(4)
, wherein R is as defined above, and thiocyanate of the formula:
Mxe2x80x94SCNxe2x80x83xe2x80x83(5)
, wherein M represents alkali metal, in the presence of an acid catalyst in a lower alcohol solvent to prepare a 1-substituted 2-mercapto-5-hydroxymethylimidazole of the formula: 
, wherein R is as defined above; and,
reacting the compound of the formula (2) in the presence of a transition metal catalyst and an oxidizing agent in a solvent.
As for the substituent xe2x80x9cRxe2x80x9d, however, any conventional substituents other than those as mentioned above may be applied without any explicit indication.
The term xe2x80x9calkylxe2x80x9d as used herein includes straight or branched chain alkyl.
The preparation process according to the present invention comprises 2 steps. The first step is that a 1-substituted 2-mercapto-5-hydroxymethylimidazole of the formula (2) is prepared by reacting 1,3-dihydroxyacetone dimer of the formula (3) with an acid addition salt of amine of the formula (4) and thiocyanate of the formula (5). The second step is that a 1-substituted 5-hydroxymethylimidazole of the formula (1) is prepared from the above compound of the formula (2) via oxidative desulfurization.
Therefore, the present invention relates to a process for preparing a 1-substituted 5-hydroxymethylimidazole of the formula: 
, wherein R is as defined above,
by the reaction of compound of the formula: 
, wherein R is as defined above,
in the presence of a transition metal catalyst and an oxidizing agent in a solvent.
Hereinafter, each step of the present process will be explained in detail.
In Step 1, a 1-substituted 2-mercapto-5-hydroxymethylimidazole of the formula 
, wherein R is as defined above,
is prepared by reacting 1,3-dihydroxyacetone dimer of the formula: 
, with an acid addition salt of amine of the formula:
RNH2xe2x80x83xe2x80x83(4)
, wherein R is as defined above, and
thiocyanate of the formula:
Mxe2x80x94SCNxe2x80x83xe2x80x83(5)
, wherein M is as defined above,
in the presence of an acid catalyst in a lower alcohol solvent.
The above reaction is depicted in the following Reaction Scheme (1): 
, wherein M and R are each as defined above.
The formation mechanism of imidazole compound of the formula (2) is depicted below(vide infra). Iminium intermediate is formed from dihydroxyacetone and amine, and tautomerized to xcex1-aminoaldehyde intermediate, which reacts with thiocyanate to give urea intermediate. Intramolecular cyclization and dehydration should afford compound of the formula (2). 
In the above reaction scheme, R is as defined above.
Since it is assumed that impurity material should be formed by the reaction of reactive xcex1-aminoaldehyde intermediate and excessive amine, control of the concentration of free amine in a suitable level is thought to be the key factor for clean reaction. Therefore, in the present invention, the problems of the previous method are removed by lowering the concentration of free amine by the employment of an acid addition salt of amine.
More specifically, to prepare a 1-substituted 2-mercapto-5-hydroxymethylimidazole of the formula (2), 1,3-dihydroxyacetone dimer of the formula (3), an acid addition salt of amine of the formula (4) and thiocyanate of the formula (5) are mixed in a mixture of lower alcohol and organic acid.
In the above reaction, the molar ratio of the 1,3-dihydroxyacetone dimer of the formula (3) to the acid addition salt of amine of the formula (4) is 0.5xcx9c2:1, preferably, 1xcx9c1.5:1. The molar ratio of the thiocyanate of the formula (5) to the acid addition salt of amine of the formula (4) is 1xcx9c3:1, preferably, 1xcx9c2:1.
As the acid addition salt of amine of the formula (4) in the above reaction, on ammonium halide is preferable and ammonium chloride is most preferable. In addition., as thiocyanate of the formula (5), potassium thiocyanate is preferable.
The acid addition salt of amine of the formula (4) in the above reaction may be commercially available or prepared with ease according to the known procedure. In some cases, it can be prepared by introducing hydrohalogen gas into amine in an equimolar amount.
As the reaction solvent, straight or branched chain lower alcohol having from 1 to 4 carbon atom(s), or a mixture thereof is preferable. More preferably, iso-propanol or n-butanol may be used.
As the reaction catalyst, acetic acid, propionic acid or any other conventional organic acids may be used preferably.
The reaction temperature may be 10 to 100xc2x0 C., preferably 20 to 80xc2x0 C.
In Step 2, a 1-substituted 5-hydroxymethylimidazole of the formula: 
, wherein R is as defined above,
is prepared by reacting a 1-substituted 2-mercapto-5-hydroxymethylimidazole of the formula: 
, wherein R is as defined above,
in the presence of a transition metal catalyst and an oxidizing agent such as hydrogen peroxide, etc. in a solvent.
The above reaction step is explained more specifically as follows.
A 1-substituted 2-mercapto-5-hydroxymethylimidazole of the formula (2) is reacted in the presence of oxidizing agent and the catalytic amount of transition metal in water, any other aqueous solvent or a mixture thereof at room temperature or the elevated temperature. In accordance with the above process, the 1-substituted 2-mercapto-5-hydroxy-methylimidazole can be converted into a 1-substituted 5-hydroxymethyl imidazole of the formula (1) with ease.
As the catalyst to be used in the above step, several transition metals with oxidizing ability such as vanadium, chromium, molybdenum, manganese, tungsten, rhenium, ruthenium, osmium, etc. may be used. Among them, rhenium, ruthenium, osmium, etc. have a drawback due to their high cost, and vanadium, chromium, manganese, tungsten, etc. are preferable because of their relatively low cost. More preferable is tungstic acid (H2WO4), vanadium pentoxide (V2O5) or vanadyl sulfate (VOSO4) The molar ratio of the transition metal catalyst such as tungstic acid (H2WO4), vanadium pentoxide (V2O5) or vanadyl sulfate (VOSO4) to the compound of the formula (2) is generally 0.001xcx9c0.2:1, preferably 0.001xcx9c0.02:1.
As the useful oxidizing agent in the present invention, hydrogen peroxide, alkyl hydrogen peroxide(such as t-butyl hydrogen peroxide etc.) or alkaline hypochlorite (sodium or calcium salt) is preferable. More preferable is 10xcx9c30% hydrogen peroxide They are used in an amount of 3 to 10 molar equivalents with respect to compound of the formula (1).
As the reaction solvent, water or any other aqueous solvent, preferably, lower alcohol or a mixture thereof may be used. The most preferable is water, methanol, ethanol or a mixture thereof.
The reaction temperature may be 20 to 100xc2x0 C., preferably 40 to 70xc2x0 C., more preferably 50 to 70xc2x0 C. Generally, the reaction is performed until a 1-substituted 2-mercapto-5-hydroxymethylimidazole of the formula (2) is completely converted into a 1-substituted 5-hydroxymethylimidazole of the formula (1), preferably, for 2 to 6 hours.
Upon the completion of the reaction, the reaction mixture may be simply neutralized and then, the resulting solid may be filtered. Alternatively, the reaction mixture may be extracted with a suitable solvent such as dichloromethane or chloroform and if necessary, further purified by treatment with a suitable solvent such as n-hexane or isopropyl ether Accordingly, the desired compound, i.e., 1-substituted 5-hydroxymethylimidazole of the formula (1) may be easily recovered from the reaction mixture in high purity.